1. Field of the Invention
This invention relates generally to the field of noninvasive glucose measurement. More particularly, the invention relates to control of optical properties of the sampling site to improve reliability of a noninvasive glucose measurement.
2. Background Information
Diabetes is a chronic disease involving the improper production and utilization of insulin, a hormone that facilitates glucose uptake into cells. While a precise cause of diabetes is unknown, both genetic and environmental factors such as obesity and lack of exercise appear to play roles. Persons with diabetes have increased health risk in three broad categories: cardiovascular heart disease, retinopathy, and neuropathy. Potential disease complications include heart disease and stroke, high blood pressure, kidney disease, neuropathy, retinopathy, diabetic ketoacidosis, skin conditions, gum disease, impotence, and fetal complications.
Diabetes Prevalence and Trends
The incidence of diabetes is both common and on the increase, making the disease a leading cause of death and disability worldwide. The World Health Organization (WHO) estimates that diabetes currently afflicts one hundred fifty-four million people worldwide. Fifty-four million people with diabetes live in developed countries. The WHO estimates that the incidence of diabetes will grow to three hundred million by the year 2025. In the United States, 15.7 million people or 5.9% of the population are estimated to have diabetes. Within the United States, the prevalence of adults diagnosed with diabetes increased by six percent in 1999 and rose by thirty-three percent between 1990 and 1998. This corresponds to approximately eight hundred thousand new cases every year in America. The estimated total cost to the United States economy exceeds $90 billion per year. National Institutes of Health, Diabetes Statistics, Publication No. 98-3926, Bethesda Md. (1997).
Long-term clinical studies show that the onset of diabetes related complications can be significantly reduced through proper control of blood glucose levels. The Diabetes Control and Complications Trial Research Group, The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus, N Eng J of Med, 329:977–86 (1993); and 1 U.K. Prospective Diabetes Study (UKPDS) Group, Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes, Lancet, 352:837–853 (1998); and 1 Y. Ohkubo, H. Kishikawa, E. Araki, T. Miyata, S. Isami, S. Motoyoshi, Y. Kojima, N. Furuyoshi, M. Shichizi, Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study, Diabetes Res Clin Pract, 28:103–117 (1995).
A vital element of diabetes management is the self-monitoring of blood glucose levels in the home environment. However, current monitoring techniques discourage regular use due to the inconvenient and painful nature of drawing blood through the skin prior to analysis. See The Diabetes Control and Complication Trial Research Group, supra. As a result, noninvasive measurement of glucose has been identified as a beneficial development for the management of diabetes. Implantable glucose analyzers eventually coupled to an insulin delivery system providing an artificial pancreas are also being pursued.
Glucose Measurement: History, Approaches, and Technologies
The treatment of diabetes has progressed through several stages. The combined development of insulin therapy and the development of devices for the self-monitoring of blood glucose in the home led to a radical improvement in the lives of individuals afflicted with diabetes. Self-monitoring of blood glucose has progressed through multiple stages from early testing that used urine samples to the current standard of invasive finger stick samples that are more accurate but somewhat painful. The development of alternative site glucose measurement technology has somewhat mitigated the pain aspects, but poses a biohazard. Alternate site blood glucose concentration levels are also known to differ from those taken at the fingertip during periods when glucose concentrations are rapidly changing. The difference is related to circulatory transport of glucose to peripheral tissues: Alternate site tissue sites with lower blood perfusion than the finger will exhibit a delay in the rise and fall of glucose levels when compared with finger blood glucose.
Current research is focused on the development of noninvasive technologies that will totally eliminate the pain associated with glucose determination and fluid biohazard issues. Another important area of research involves the combination of automated glucose measurement and insulin therapy. Progress has been reported in the research on implantable or full-loop systems that have been proposed to incorporate both glucose measurement and control through automated insulin delivery. In the interim, a device that provides noninvasive, automatic, or (nearly) continuous measurement of glucose levels would clearly be useful to those afflicted with diabetes. Various systems have been developed with this goal in mind. J. Tamada, S. Garg, L. Jovanovic, K. Pitzer, S. Fermi, R Potts, Noninvasive glucose monitoring comprehensive clinical results, JAMA, 282:1839–1844 (1999) describe a minimally-invasive monitoring system reported that provides three readings of interstitial fluid glucose per hour, each delayed by up to fifteen minutes due to the sample acquisition process. The measurement is made through an electrochemical-enzymatic sensor on a sample of interstitial fluid that is drawn through the skin using an iontophoresis technique. Other approaches, such as the continuous monitoring system reported by T. Gross, B. Bode, D. Einhorn, D. Kayne, J. Reed, N. White and J. Mastrototaro, Performance evaluation of the Minimed® continuous glucose monitoring system during patient home use, Diabetes Technology & Therapeutics, Vol. 2, Num. 1, (2000) involve the surgical implantation of a sensor in tissue. Health risks due to sensor implantation or measurement delay remain as obstacles to efficacious use of these devices in directing insulin therapy. To date, a fully noninvasive alternative has not been approved by the FDA.
Noninvasive Glucose Measurement
There exist a number of noninvasive approaches for glucose determination. These approaches vary widely, but have at least two common steps. First, an apparatus is utilized to acquire a reading from the body without obtaining a biological sample. Second, an algorithm is utilized to convert this reading into a glucose determination.
A generalized approach to noninvasive glucose measurement utilizes some form of spectroscopy to acquire the signal or spectrum from a measurement site on the subject's body. Techniques include but are not limited to: impedance, Raman, and fluorescence; as well as techniques using light, from the ultraviolet through the infrared [ultraviolet (200 to 400 nm), visible (400 to 700 nm), near-IR (700 to 2500 nm or 14,286 to 4000 cm−1), infrared (2500 to 14,285 nm or 4000–700 cm−1)]. A specific near infrared range for noninvasive glucose determination in diffuse reflectance mode is about 1100 to 2500 nm or ranges or sets of ranges therein. K. Hazen, Glucose Determination in Biological Matrices Using Near-infrared Spectroscopy, doctoral dissertation, University of Iowa (1995). It is important to note, that these techniques are distinct from the minimally invasive techniques listed above in that the sample analyzed is a portion of the human body in situ, not a biological sample extracted from the human body.
Potential sites for the noninvasive measurement have been identified from the ear lobe, oral mucosa, arm, and eye to the fingertip. It is important to note that noninvasive techniques do not have to be based upon spectroscopy. Within the context of the invention, any device that reads glucose from the body without penetrating the skin and collecting a biological sample is classified as a noninvasive glucose analyzer.
To date, noninvasive glucose measurement has conventionally employed a direct measurement approach, in which the net analyte signal due to the absorption of light by glucose in the tissue is used to calculate the glucose concentration. There exist formidable challenges to the development of reliable methods of glucose measurement using a direct approach. Among these challenges are the size of the glucose signal relative to the spectral background, the heterogeneity of the sample, the multi-layered structure of the skin, the rapid variation related to hydration levels, changes in the volume fraction of blood in the tissue, hormonal stimulation, temperature fluctuations, and blood analyte levels. Control of the optical properties of the sample site is essential to the success of any method of noninvasive glucose measurement using a direct measurement approach.
Calibration And Utilization Of Noninvasive Glucose Meters
One noninvasive technology, near-infrared spectroscopy, provides the opportunity for both frequent and painless noninvasive measurement of glucose. This approach involves the illumination of a spot on the body with near-infrared (NIR) electromagnetic radiation, light in the wavelength range 700 to 2500 nm. The light is partially absorbed and scattered, according to its interaction with the constituents of the tissue. The actual tissue volume that is sampled is the portion of irradiated tissue from which light is collected and transported to the spectrometer detection system.
Generation of a suitable calibration involves development of a mathematical relationship between an in vivo near-infrared spectral measurement and a corresponding reference blood glucose concentration. The model generation process includes the collection of a multiplicity of matched spectrum/reference glucose pairs followed by the calculation of a regression model between the multiple independent variables contained in each spectral vector and the associated single dependent reference glucose value. Reference blood glucose values are typically obtained directly through the use of measurement tools like the HEMOCUE (YSI, Inc., Yellow Springs Ohio) or any other reliable invasive glucose analyzer.
The Beer-Lambert Law, equation 1 infra, defines a proportionality constant between glucose concentration and spectral light absorbed at a single spectral wavelength in the special case where no interfering spectral signatures are present. In equation 1, A is the scalar absorbance measurement at a given wavelength of light, ε is the molar absorptivity associated with the molecule of interest at the same given wavelength, b is the distance (or pathlength) that the light travels through the sample, and C is the concentration of the molecule of interest (glucose).A=εbC
A number of interferences do exist for the near-infrared measurement making the correction for these interferences necessary. Correction is achieved by using multiple wavelengths in each spectrum in a multivariate regression model. Such a model is proven means for compensation of spectral interferences, requiring some measure of uniqueness in the spectral signature of the glucose.=C
In equation 2, boldface type denotes vector variables. The expression is interpreted as the outer product of the regression vector k and the absorbance spectrum vector A, consisting of the absorbance at a multiplicity of selected wavelengths, is equal to the glucose concentration C of the sample.
Common multivariate approaches that can be used to solve the equation 2 for the regression vector k can include partial least squares (PLS) and principal component regression (PCR). Nonparametric methods of calibration such as neural networks and multiple adaptive regression splines (MARS) can also be used to model an expression analogous to equation 2 in the case where Beer's law deviations are present and the relation becomes nonlinear.
Because every method of glucose measurement has error, it is beneficial that the primary reference device, which is used to develop and evaluate noninvasive calibrations for blood glucose, be as accurate as possible to minimize the uncertainty in the model. An instrument with a percentage error of five or less is most desirable. An instrument having a percentage error of up to ten would be suitable, though the error of the device being calibrated may increase.
Instrumentation
Noninvasive
A number of technologies have been proposed for measuring glucose non-invasively, all of which involve some type of tissue measurement. Spectroscopy-based noninvasive glucose analyzers utilize the measured interaction of the tissue sample with electromagnetic radiation (EMR) or another type of energy input that leads to an emission of EMR to acquire the signal or spectrum. Examples include but are not limited to Nuclear Magnetic Resonance (NMR) spectroscopy, UV, visible near-infrared, mid-infrared, and far-infrared spectroscopy, tissue impedance spectroscopy, Raman spectroscopy, and fluorescence spectroscopy. The near infrared range for noninvasive glucose determination in diffuse reflectance mode is about 1100 to 2500 nm or ranges therein. Hazen (1995), supra. It is important to define noninvasive techniques as being distinct from invasive techniques in that the noninvasive sample is analyzed in-situ, as opposed to invasively extracting a biological sample through the skin for analysis. The actual tissue volume that is sampled is the portion of irradiated tissue from which light is reflected or transmitted to the spectrometer detection system. All of these techniques share the common characteristic that, as secondary calibration methods, they require a calibration, model or other transformation to convert the measured signal to an estimate of the glucose concentration using reference measurements based on a primary method, such as invasive measurements from samples of venous or capillary blood.
A number of spectrometer configurations exist for collecting noninvasive spectra from regions of the body. Typically a spectrometer has one or more beam paths from a source to a detector. A light source may include a blackbody source, a tungsten-halogen source, one or more LED's, or one or more laser diodes. For multi-wavelength spectrometers a wavelength selection device may be utilized or a series of optical filters may be utilized for wavelength selection. Wavelength selection devices include dispersive elements such as prisms, and gratings of various types. Nondispersive wavelength selective devices include interferometers, successive illumination of the elements of an LED array, and wavelength selective filters. Detectors may be in the form of one or more single element detectors or one or more arrays or bundles of detectors. Detector materials are selected to obtain the desired signal measurement characteristics over the necessary wavelength ranges. Light collection optics such as fiber optics, lenses, and mirrors are commonly utilized in various configurations within a spectrometer to direct light from the source to the detector by way of a sample.
The interface of the glucose analyzer to the tissue includes a patient interface module for directing light into and collecting light from the tissue measurement site. Optical conduits for directing and collecting light may include a light pipe, fiber optics, a focusing lens system, or a light directing mirror system.
The scanning of the tissue can be done continuously when pulsation effects do not affect the tissue area being tested, or the scanning can be done intermittently between pulses. The collected signal (near-infrared radiation in this case) is converted to a voltage and sampled through an analog-to-digital converter for analysis on a microprocessor based system and the result displayed.
Related Skin Physiology
One of the primary functions of cutaneous skin is to provide a means for thermoregulatory control of body temperature. Blood at approximately 98° F. is pumped to the outer skin layers to provide nutrients, is a means for waste removal, and is a mechanism for thermoregulatory control. In the case of warm ambient temperatures, heat can be dissipated from the core of the body when increased blood flow is combined with the cooling effects of sweat evaporation on the skin surface. In the case of cool ambient temperatures, heat can also be used to warm a cool skin surface, but rapid heat loss associated with touching cold objects is limited by constrictively reducing blood flow to the superficial tissues. These thermoregulatory mechanisms typically use constriction or dilation of capillary vessels and the concomitant variation in blood flow to control the potential for heat transfer to and from the body. Capillary diameters can vary tenfold during these processes.
A tenfold variation in capillary vessel diameter can lead to substantial changes in the composition and optical properties of the tissue. Such variation in the measured tissue sample can lead to poor sampling precision over a sequential series of measurements. Sample normalization of a varying signal derived from the heterogeneous, layered structure of skin can be of limited effectiveness due to spectral nonlinearities imposed by the compositional variation of the layers and the sequential path of light through the various layers of skin. Specifically, the broadband source light is filtered uniquely in the wavelength domain by each skin layer according to the changing compositions and varying optical densities that result with a perfusion shift in the tissue. The result is that the optical sample is destabilized in a nonlinear manner that is difficult or impossible to normalize with a high degree of accuracy. It follows that the modeling of glucose concentration will be most efficacious under the conditions that variations in the optical properties of the sample are minimized excepting where changes in the optical properties are a direct result of glucose variation.
Accuracy and robustness are improved with thermal control in the case of either a conventional direct measurement or an indirect measurement, described below, of blood glucose. Thermally or mechanically stimulated changes in optical properties will complicate direct noninvasive glucose determinations. Thermal perturbations are addressed herein using the knowledge of human vascular response to heat and cold and by limiting temperature transients due to skin contact with objects that differ by more than 5 degrees F. from typical resting skin temperatures of 85–95° F.